WO2018191528A1 - Méthode de pronostic et de réduction des maladies cardiovasculaires chez les patients atteints de maladies rénales - Google Patents

Méthode de pronostic et de réduction des maladies cardiovasculaires chez les patients atteints de maladies rénales Download PDF

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Publication number
WO2018191528A1
WO2018191528A1 PCT/US2018/027347 US2018027347W WO2018191528A1 WO 2018191528 A1 WO2018191528 A1 WO 2018191528A1 US 2018027347 W US2018027347 W US 2018027347W WO 2018191528 A1 WO2018191528 A1 WO 2018191528A1
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patients
diseases
kidney
sample
kidney diseases
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PCT/US2018/027347
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English (en)
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Wan-lin WU
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Chi-Hua Foundation
WU, Tiffany
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Priority to EP18783893.3A priority Critical patent/EP3610033A4/fr
Publication of WO2018191528A1 publication Critical patent/WO2018191528A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/5308—Immunoassay; Biospecific binding assay; Materials therefor for analytes not provided for elsewhere, e.g. nucleic acids, uric acid, worms, mites
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/34—Spatial arrangement of the modifications
    • C12N2310/341—Gapmers, i.e. of the type ===---===
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/118—Prognosis of disease development
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/158—Expression markers
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/178—Oligonucleotides characterized by their use miRNA, siRNA or ncRNA
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis

Definitions

  • the present invention relates to a method for prognosing and reducing cardiovascular disease in patients with kidney diseases, especially the biomarker provided by the present disclosure may prognose the risk of having cardiovascular disease in patients with kidney diseases, and reduce the chance to have cardiovascular disease in patients with kidney diseases through inhibiting the biomarker.
  • Inflammation may induce the generation of cytokines (T F-a, IL- ⁇ , etc.), cell adhesion molecules (VCAM-1, ICAM-1, E-selectin, etc.), chemokine (MCP-1), and inflammation-related proteins, wherein the cell adhesion molecules expressed by endothelial cells may facilitate the adhesion of monocyte cells and endothelial cells.
  • Monocyte cells may further penetrate the endothelial cells into the inner membrane of vessel, and become macrophage.
  • the macrophage unlimitedly intakes a huge amount of oxidized low-density lipoprotein cholesterol to form foam cells.
  • the process is being considered as a primary and critical step in the formation of atherosclerosis. Therefore, the cell adhesion molecules may be used as an indicator to prognose cardiovascular diseases in the current research.
  • cardiovascular diseases including sudden cardiac arrest, acute myocardial infraction, arrhythmia and other forms of cardiovascular events.
  • Patients with chronic kidney diseases and uremic patients undergoing hemodialysis commonly face the issues comprising hypertension, ectopic calcification, bone disease, uremic toxins, chronic inflammation, and high blood sugar, etc., and further with instability of dyslipidemia or vascular plaque, thereby increasing the risk of cardiovascular diseases. Therefore, the researchers in this field all devote to find reliable biomarkers to facilitate early diagnosis and to predict the prognosis of cardiovascular diseases in patients with chronic kidney diseases and uremia.
  • IncRNAs Long Non-Coding RNAs
  • studies have suggested that IncRNAs are involved in the regulation of cellular function, and IncRNAs function critically in regulating gene expression, maintaining genome integrity, compensating gene dosage, genome imprinting, mRNA processing, and cell differentiation and development.
  • Aberrantly expressed IncRNAs contribute to the development of many diseases including cancers, immune diseases and neurological disorders, would occur.
  • Endothelial nitric oxide synthase may generate nitric oxide (NO), which is important for normal endothelial and vascular function.
  • NO nitric oxide
  • the amount of NO in the vasculature is altered with atherosclerosis and many cardiovascular diseases. Therefore, the abnormality of eNOS gene expression may affect the risk of atherosclerosis in an individual.
  • Some people use eNOS as a diagnostic marker for atherosclerosis.
  • eNOS functions by generating NO in blood vessel
  • eNOS is one of the most attractive therapeutic target for cardiovascular diseases.
  • KLF2 Kriippel-like transcription factors 2
  • KLF2 belongs to transcription factors of Kriippel family. KLF2 may improve the movement of perivascular cells and smooth muscle cells in the late stage of vessel development to form vessel wall structure, further to concrete neovascularization. KLF2 are involved in the maintenance of normal vascular functions, such as anti-inflammation, anticoagulation, vasodilation, vascularization and regulation of endothelial cell secretion, wherein in the anticoagulation and vasodilation, KLF2 increases the expression of eNOS to maintain normal physiological functions. In various vascular diseases, such as atherosclerosis, diabetes and transient ischemic attack, the expression of KLF2 deceases. Therefore, increasing the expression of KLF2 may be considered as a method to treat vascular diseases.
  • the purpose of the present disclosure provides a method for prognosing and reducing cardiovascular diseases in patients with kidney diseases. According to each and every research result, it is confirmed that the screened IncRNA of the present disclosure may prognose patients with kidney diseases belonging to a high-risk group to have cardiovascular diseases.
  • the technique is analyzing the expression of the specific target, IncRNA, in the blood sample of the patients with kidney disease, such as one or more combinations selected from DKFZP434I0714, KCNJ2AS1, LOC256880, LOC644656, FAM86FP, FAM66D, LOC100289511 and HTR7P1. If the expression of the target, IncRNA, in the patients with kidney diseases is higher than the average, the patient belongs to the high-risk group of having cardiovascular diseases in the future.
  • the other purpose of the present disclosure provides a method for reducing cardiovascular diseases in patients with kidney diseases.
  • the technical feature is utilizing the technology of antisense DNA oligos or similar agents to inhibit the expression of target IncRNAs in patient with kidney diseases, in order to decrease possibility of patient with kidney diseases to have cardiovascular diseases .
  • Figure 1 shows the comparison of IncRNA expression in plasma sample between patients with kidney diseases at terminal stage who have cardiovascular diseases and patients with kidney diseases at terminal stage who have no cardiovascular diseases.
  • Figure 2 shows the results of the expression of target IncRNA in Embodiment 2 as in bitmap.
  • Figure 3 shows Kaplan-Meier curve of the expression of biomarker DKFZP434I0714 in patients with kidney disease and survival times in Embodiment 3.
  • Figure 4 shows the results of the inhibition to DKFZP434I0714 in Embodiment 4.
  • the present disclosure provides a method for prognosing and reducing cardiovascular diseases in patients with kidney diseases, comprising steps of: [0023] The plasma from blood sample in test sample of the present embodiment, and these samples have been tracked for five years and collected:
  • Sample A Healthy people, 13 counts;
  • Sample B Patients with kidney failure, 19 counts;
  • Sample C Patients with kidney diseases at terminal stage who have no cardiovascular diseases, 43 counts;
  • Sample D Patients with kidney diseases at terminal stage who have cardiovascular diseases, 36 counts.
  • RNA Sequencing technology to analyze the difference between each sample, and analyze potential biomarkers. Furthermore, utilize polymerase chain reaction and analytic software to analyze.
  • the software used in the present embodiment is Multiple Experiment Viewer (MeV).
  • Embodiment 1 To confirm that the biomarker IncRNA acquired from Embodiment 1 is positively correlated with patients with kidney diseases having cardiovascular diseases, a further expression analysis is being conducted on eight specific IncRNAs in Embodiment 1.
  • the present embodiment tracks the correlation between the present biomarker, IncRNA, in the patients with kidney diseases and the survival ratio for a long period of time.
  • STATA 14.0 SudCorp, TX
  • the survival ratio of the present embodiment is adverse cardiovascular events or death caused by cardiovascular diseases in patients with kidney diseases.
  • the expression of IncRNA, DKFZP434I0714 is closely associated with the survival ratio of the patients with kidney diseases to cardiovascular diseases. During these fifty months, when the expression of IncRNA DKFZP434I0714 increases, the survival ratio of the patients with kidney diseases decreases; when the expression of IncRNA, DKFZP434I0714, decreases, the survival ratio of the patients with kidney diseases is relatively higher.
  • the applicants deem: when the expressions of the eight IncRNAs, including DKFZP434I0714, KCNJ2AS1, LOC256880, LOC644656, FAM86FP, FAM66D, LOC100289511 and HTR7P1, from patients with kidney diseases increases, the patients with kidney diseases belong to the high-risk group to have cardiovascular diseases. Therefore, the eight IncRNAs may be used as a biomarker to determine whether the patients with kidney diseases belong to the high-risk group to have cardiovascular diseases.
  • the experimental method to determine expression of eight IncRNAs can be performed with, but not limited to: reverse transcriptase-polymerase chain reaction (RT-PCR), quantitative real-time PCR (qPCR), digital droplet PCR (ddPCR), microarray, serial analysis of gene expression (SAGE), next-generation RNA sequencing, massively parallel signature sequencing (MPSS), in situ hybridization (ISH), mass spectrometry (MS), RNA pull-down and the like.
  • RT-PCR reverse transcriptase-polymerase chain reaction
  • qPCR quantitative real-time PCR
  • ddPCR digital droplet PCR
  • microarray microarray
  • SAGE serial analysis of gene expression
  • MPSS massively parallel signature sequencing
  • ISH in situ hybridization
  • MS mass spectrometry
  • the present invention provides a method for reducing cardiovascular diseases in patients with kidney diseases, and its technique is a known gene inhibition technology, locked nucleic acid (LNA) Gapmer.
  • LNA locked nucleic acid
  • the present embodiment utilizes LNA Gapmer to inhibit the expression of IncRNA DKFZP434I0714 in human aortic endothelial cells, HAEC, and determine the expressions of known cardiovascular disease factors, ICAM1 and VCAMl, and the expressions of eNOS and KLF2 simultaneously.

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  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
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Abstract

La présente invention concerne une méthode permettant de pronostiquer et de réduire les maladies cardiovasculaires chez les patients atteints de maladies rénales, la méthode comprenant l'obtention d'un échantillon biologique d'une personne saine et d'un échantillon biologique d'un patient atteint de maladie rénale, la détection individuelle de l'expression de biomarqueurs d'ARNInc spécifiques, tels qu'une ou plusieurs combinaisons de DKFZP434I0714, KCNJ2AS1, LOC256880, LOC644656, FAM86FP, FAM66D, LOC100289511, et HTR7P1, la comparaison des expressions entre les échantillons des personnes saines et les échantillons des patients atteints de maladies rénales pour obtenir un rapport, et le pronostic selon lequel les patients atteints de maladies rénales appartiennent ou non à un groupe à risque élevé de maladies cardiovasculaires sur la base dudit rapport. De plus, la méthode réduit la possibilité de maladies cardiovasculaires chez les patients atteints de maladies rénales par une technologie d'inhibition.
PCT/US2018/027347 2017-04-13 2018-04-12 Méthode de pronostic et de réduction des maladies cardiovasculaires chez les patients atteints de maladies rénales WO2018191528A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130178428A1 (en) * 2011-11-30 2013-07-11 Dave S.B. HOON Long noncoding rna (lncrna) as a biomarker and therapeutic marker in cancer
WO2016091888A2 (fr) * 2014-12-08 2016-06-16 Institut National De La Sante Et De La Recherche Medicale (Inserm) Procédés, kits et compositions pour le phénotypage du comportement d'un adénocarcinome canalaire pancréatique par transcriptomique
WO2016146996A1 (fr) * 2015-03-16 2016-09-22 The University Court Of The University Of Edinburgh Matériels et méthodes pour le traitement de maladies vasculaires
WO2017017253A1 (fr) * 2015-07-29 2017-02-02 Ifom - Fondazione Istituto Firc Di Oncologia Molecolare Oligonucléotides thérapeutiques

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102286464B (zh) * 2011-06-30 2013-07-17 眭维国 尿毒症长链非编码核糖核酸差异性表达图谱模型及其构建方法
EP3083997B1 (fr) * 2013-12-20 2020-07-29 Université de Lausanne Utilisations des longs arn non codants pour le diagnostic, le pronostic et le traitement des cardiopathies et dans le cadre de la médecine régénérative
EP2985351B1 (fr) * 2014-08-14 2017-10-04 Medizinische Hochschule Hannover Un arn non-codant circulant pour prognostiquer la mortalité d'un patient avec défaillance rénale

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130178428A1 (en) * 2011-11-30 2013-07-11 Dave S.B. HOON Long noncoding rna (lncrna) as a biomarker and therapeutic marker in cancer
WO2016091888A2 (fr) * 2014-12-08 2016-06-16 Institut National De La Sante Et De La Recherche Medicale (Inserm) Procédés, kits et compositions pour le phénotypage du comportement d'un adénocarcinome canalaire pancréatique par transcriptomique
WO2016146996A1 (fr) * 2015-03-16 2016-09-22 The University Court Of The University Of Edinburgh Matériels et méthodes pour le traitement de maladies vasculaires
WO2017017253A1 (fr) * 2015-07-29 2017-02-02 Ifom - Fondazione Istituto Firc Di Oncologia Molecolare Oligonucléotides thérapeutiques

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EP3610033A1 (fr) 2020-02-19
US20190127795A1 (en) 2019-05-02

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